There is no effective pharmacological treatment for cocaine dependence despite over two decades of research. Pre-clinical studies have elucidated the importance of glutaminergic and dopaminergic circuits among the nucleus accumbens, ventral tegmental area, and prefrontal cortex. These studies have indicated that repeated cocaine administration reduces synaptic glutamate. Most synaptic glutamate arises from nonvesicular release, and specifically from the cysteine/glutamate antiporter. This exchanger is a plasma membrane-bound sodium dependent anionic amino acid transporter that exchanges extra cellular cystine for intra cellular glutamate. Repeated cocaine administration impairs the cystine glutamate exchanger, lowering extracellular glutamate levels. Reverse dialysis of cysteine restores diminished basal glutamate levels in the nucleus accumbens. Systemic administration of cysteine pro drugs such as N-acetylcysteine (NAC) also normalizes extracellular glutamate and blocks behavioral reinstatement by cocaine. MAC is FDA-approved for the treatment of cystic fibrosis and acetaminophen overdose. We studied 13 non-treatment seeking cocaine dependent subjects who were given 600 mg of NAC orally twice daily and measured side effects, tolerability, self-reported cocaine craving, cocaine withdrawal symptoms, and electrophysiologic measures of cue reactivity. Number of side effects did not differ between NAC and placebo (p=0.29). Craving ratings suggested that when subjects were treated with NAC, cravings dropped (p=0.05) while placebo subjects did not show a significant drop in craving. NAC significantly reduced cocaine withdrawal symptoms as measured by the Cocaine Severity Assessment (p<0.05). In the cue reactivity paradigm, subjects showed comparable responses to both cocaine and neutral slides;in the placebo condition, subjects showed a higher level of responding to cocaine relative to neutral stimuli (p=0.052). Convincing pre-clinical molecular and behavioral studies support the use of NAC to treat cocaine dependence. We have preliminary human laboratory data suggesting that NAC reduces craving, cocaine withdrawal symptoms, and possibly skin conductance cue reactivity. We have received an IND from the FDA to conduct a double blind, phase II trial of NAC plus cognitive-behavioral therapy (CBT) in the treatment of cocaine dependence. The primary objective to this proposal include: 1) to determine the efficacy of two doses (1200, 2400 mg) of NAC orally with CBT as compared to placebo and CBT in treating cocaine dependence (N=282) as measured by self-report and validated by quantitative urine drug screens;2) to determine the safety of NAC vs. placebo;and 3) to study cocaine craving/cue reactivity and withdrawal symptoms in subjects taking NAC or placebo.